The following description of the background of the invention is provided simply as an aid in understanding the invention and is not admitted to describe or constitute prior art to the invention.
Individuals with inborn errors of metabolism (IEM) can, in many cases, be identified by the presence of abnormal metabolites which are either non-existent or present in only very small amounts as compared to the urine of normal individuals. Such markers of metabolism include organic acids, which constitute a large variety of individual compounds. For example, inborn errors of metabolism associated with increased excretion of various acyl glycines, including isovaleryl, crotonyl, 3-methylcrotonyl, butyrol, 2-methylbutyryl and suberoyl glycines is known. Analyses of these glycines in human plasma and urine is used for the diagnosis of diseases such as medium chain acyl-CoA dehydrogenase deficiency, an error in mitochondrial β-oxidation of straight chain fatty acid, carboxylase deficiency, and 2-methylacetoacetyl CoA thiolase deficiency, as well as isovaleric acidaemia, propionic acidaemia and isovaleric acidaemia. See e.g., Zytkovicz et al., Clin Chem 47(11): 1945-1955 (2001).
Quantitative analyses of organic acids in urine or serum are usually performed by the procedures of extracting the acids from biological samples, chemical derivatization of extracted acids, and finally separation and detection of derivatized acids by gas chromatography-mass spectrometry (GC-MS) or in some cases by tandem mass spectrometry (MS/MS). See e.g., Sweetman, In (Homes, Ed.) “Techniques in diagnostic human biochemical genetics” Wiley-Liss, New York, page 143-174 (1991); Kushnir et al., Clin Chem 47(11): 1993-2002 (2002). Internal standards are used in some cases to predict the loss of an organic acid from processing so that the starting amount of the acid in the sample may be accurately calculated. However, there remains a continuing need for a wide range labeled organic acid internal standards to enable more accurate methodologies with greater ease of use in providing high throughput and lower overall cost detection of signature IEM.